Effects of Sitagliptin on 24-H Glycemic Changes in Japanese Patients with Type 2 Diabetes Assessed Using Continuous Glucose Monitoring

Introduction

T he treatment goals of diabetes are to prevent complications and inhibit their progression by controlling the glycemic level at a level similar to that in healthy people. Hemoglobin A1c (HbA1c) has been used as a surrogate marker of glycemic control or a surrogate end point in several large-scale clinical studies. However, the DECODE study ¹ and the STOP-NIDDM study ² showed that patients with postprandial hyperglycemia had a higher risk of cardiovascular events, even when their fasting glucose levels were the same as those in patients without hyperglycemia. These studies also showed that it is difficult to monitor glycemic control with HbA1c only because HbA1c is a marker of the average glycemic level. Based on these findings, the International Diabetes Federation announced the Guidelines for Management of Postmeal Glucose in 2007. ³ These guidelines indicated the importance of management of postprandial hyperglycemia, which cannot be evaluated with HbA1c only, and proposed a new method of continuous glucose monitoring (CGM) to evaluate postprandial glucose level.

In CGM, the average glucose level is measured at an interval of 1–5 min. This allows monitoring of postprandial glycemic changes, which have previously been partially monitored by conventional self-monitoring of blood glucose (SMBG). In CGM, the pattern of glycemic changes can be visualized; the 24-h glycemic fluctuation range (the time for which the glucose level is greater than or less than a certain level) can be obtained; and asymptomatic hypoglycemia, which cannot be determined by conventional methods, can be analyzed using software. These advances have improved glucose management by facilitating control of the glucose level with smaller 24-h glycemic fluctuation and less swing at the same HbA1c value.

Sitagliptin is a dipeptidyl peptidase (DPP)-4 inhibitor that enhances the activity of incretins, which then promote insulin secretion in a glucose-dependent manner, and inhibits glucagon secretion. ^{4 –7} A comparative clinical study with an α-glucosidase inhibitor showed that sitagliptin significantly improved the glucose level at 2 h after meal, the fasting blood glucose level, and HbA1c. ⁸ However, each of these parameters was measured at a single time point, and the effects of sitagliptin on 24-h glycemic changes in Japanese patients are still unclear. Therefore, in this study, we examined the effects of sitagliptin on 24-h glycemic changes using CGM in single administration or concomitant administration with another oral hypoglycemic drug.

Subjects and Methods

Study method

After the patient was admitted to the hospital, CGM was performed when the blood glucose level before a meal reached a stable level after dietary therapy alone or in combination with an oral hypoglycemic drug. CGM was performed using the CGMS^® System GOLD^™ system (Medtronic MiniMed, Northridge, CA). Glycemic changes were monitored by CGM for 4 successive days, and administration of 50 mg of sitagliptin once daily was started before breakfast on Day 3 of the 4-day observation period (Fig. 1). Based on the CGM data on Day 2 of observation and Day 2 of sitagliptin administration (Day 4 of observation), the average and SD of the 24-hour glucose level, mean amplitude of glycemic excursion (MAGE), 24-h glycemic fluctuation (total area between the 24-h mean blood glucose and continuous blood glucose curve), and time periods of hyperglycemia (glucose level >180 mg/dL) and hypoglycemia (glucose level <70 mg/dL) were determined.

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FIG. 1.

Outline of the study. Continuous glucose monitoring (CGM) was performed when the glucose level before meals reached a stable level after dietary therapy alone or combined dietary therapy and oral administration of a hypoglycemic drug. Glycemic changes were monitored using the Medtronic CGMS System GOLD for 4 successive days. Administration of sitagliptin (50 mg) once daily before breakfast was started on Day 3 of this period.

Results

The patients' background is shown in Table 1. Sitagliptin was administered to 30 subjects (20 men, 10 women) with mean age, body mass index, and HbA1c at hospital admission of 69.9 ± 5.7 years old, 25.3 ± 3.6 kg/m², and 7.6 ± 1.3% (criteria of the Japanese Diabetes Society), respectively. Fourteen subjects received sitagliptin only, and 16 received concomitant therapy with another oral hypoglycemic drug. A sulfonylurea was the most common concomitant drug.

Glycemic changes obtained by CGM before and after administration of sitagliptin are shown in Figure 2. These data are averaged over all subjects. Hyperglycemia observed after meals before administration was improved by sitagliptin. The nighttime fasting glucose level was also decreased compared with the level before administration. The average 24-h glucose level, SD of the 24-h glucose level, and 24-h glycemic fluctuation were all significantly decreased after administration, compared with these data before administration (Fig. 3). MAGE and the time period of hyperglycemia (blood glucose level >180 mg/dL) were also significantly decreased after administration of sitagliptin (Fig. 4). All of these parameters showed similar improvement in patients treated with sitagliptin alone and those that received a concomitant sulfonylurea drug.

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FIG. 2.

Changes in 24-h blood glucose before and after administration of sitagliptin. The data are averages from 30 subjects.

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FIG. 3.

(A) Average, (B) SD, and (C) fluctuation of the 24-h blood glucose level before and after administration of sitagliptin. Data are mean ± SD values. **P < 0.01, ***P < 0.001 (t test).

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FIG. 4.

(A) Mean amplitude of glucose excursions, (B) percentage period of hyperglycemia (glucose >180 mg/dL), and (C) percentage period of hypoglycemia (glucose <70 mg/dL) before and after administration of sitagliptin. Data are mean ± SD values. ***P < 0.001 (t test).

The correlation between decreases in average glucose levels after sitagliptin administration and average glucose levels before administration is shown in Figure 5. These data showed a significant negative correlation, suggesting that the decrease was greater when the average glucose level before administration was higher. A similar significant negative correlation was found between MAGE before sitagliptin administration and changes in MAGE after administration (Fig. 6). Again, this suggests that improvement of glycemic control by sitagliptin is likely to be greater in patients with high MAGE before administration.

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FIG. 5.

Correlation between average 24-h blood glucose levels before administration of sitagliptin and decreases in average 24-h blood glucose levels after administration.

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FIG. 6.

Correlation between mean amplitude of glucose excursion before administration of sitagliptin and decreases in mean amplitude of glucose excursion after administration.

Discussion

DPP-4 inhibitors increase the activity of glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide, which are endogenous incretin hormones that regulate glucose-dependent insulin and glucagon secretion, and this effect improves hyperglycemia. ⁹ Thus, whereas sulfonylureas and glinide drugs decrease the glucose level through a direct action on insulin secretion with closing of K_ATP channels of pancreatic β cells, ¹⁰ the effect of a DPP-4 inhibitor such as sitagliptin depends on the blood glucose level itself. ¹¹ In this study, the average 24-h blood glucose level was decreased by sitagliptin, and this effect was mainly due to improvement of postprandial hyperglycemia.

The glycemic changes after administration of sulfonylurea drugs to patients with type 2 diabetes suggest that these drugs decrease the average 24-h glucose level, based on the HbA1c value, but do not decrease the range of glycemic fluctuation, as well as decrease postprandial hyperglycemia and the fasting glucose level to a similar extent. ¹² Administration of sitagliptin alone and concomitant administration with a sulfonylurea drug decreased the average glucose level and improved glycemic fluctuation. Thus, sitagliptin appears to be a more appropriate drug for improvement of postprandial hyperglycemia and is also likely to improve glucose spikes, which cannot be monitored using HbA1c only, and prevent macrovascular complications.

In this study, we found a significant decrease in the time period of hyperglycemia (blood glucose level >180 mg/dL), but the period of hypoglycemia did not increase and actually showed a tendency to decrease. Vildagliptin, another DPP-4 inhibitor, has been found to significantly increase the level of glucagon in blood in a hypoglycemia clamp study. ¹³ Incretin hormones have various bioactivities other than a direct increase in insulin secretion via receptors on the pancreatic β cell membrane. ^{14 –16} Expression of a glucagon-like peptide-1 receptor has been shown in the central nervous system, ¹⁶ and a preclinical study showed that glucagon-like peptide-1 signals in the central nervous system control glucose uptake and production in the peripheral tissues. ¹⁷ Therefore, sitagliptin may also maintain homeostasis of blood glucose via the central nervous system through increased activity of incretin, in addition to having a direct action in pancreatic β cells.

The extent of the decrease in the average blood glucose level induced by sitagliptin was correlated with the average glucose level before administration. This indicates that patients with a higher glucose level before administration of sitagliptin are likely to have a greater decrease in the glucose level. These data confirm the results of Japanese and overseas clinical studies with sitagliptin, which have shown that the decrease in the glucose level is greater in patients with a higher HbA1c level before administration. ^{18 –20} The findings also support the evaluation of drug efficacy with CGM because they show that changes in the average 24-h glucose level are related to changes in HbA1c. The MAGE level before sitagliptin administration was also correlated with the decrease in MAGE after administration, which suggests that larger glycemic fluctuation may result in a greater effect of sitagliptin in maintaining the homeostasis of blood glucose.

Conclusions

The results of this study suggested that sitagliptin, a DPP-4 inhibitor, not only decreases the average blood glucose level, but also greatly improves postprandial hyperglycemia. Thus, sitagliptin can improve 24-h glucose swings, that is, maintain the homeostasis of blood glucose.